A substance found in red wine and touted as the chemical equivalent of the fountain of youth probably acts more like a wellspring of health — with warning signs.
Resveratrol, as the chemical is known, does a pretty good job of mimicking some age-defying effects found in studies of animals on calorie-restricted diets. But the substance doesn’t make animals live longer, a new study shows. Louis J. Sheehan, Esquire
At the same time, boosting levels of a key enzyme thought to be responsible for resveratrol action and for the life-extending properties of calorie restriction does protect mice fed high-fat diets from heart problems.
But a third group of researchers warns that more activity of the enzyme, called SirT1, may make brain cells vulnerable to damage.
Some scientists are optimistic that in the near future a pill with resveratrol or something like it could provide the health benefits of a very low-calorie diet. But the new research indicates the drug and the diet regimen don’t necessarily work the same way.
“You have to carefully study the reality, and the reality is, it’s complicated,” says Valter Longo, a molecular geneticist at the University of Southern California’s Andrus Gerontology Center.
For instance, two new studies show that each organ in the body may react differently to calorie restriction, to chemical mimics such as resveratrol, or to different actions of key proteins involved in controlling aging.
Those proteins, called sirtuins, are a group of enzymes found in organisms from bacteria to humans, which have been shown to regulate aging in yeast, roundworms and fruit flies. The proteins were named for the yeast protein Sir2, the first member of the family discovered.
Increasing levels of the mouse sirtuin, SirT1, prevents mice from developing heart problems and fatty livers even when they are fed high-fat diets, researchers at the University of Cincinnati College of Medicine and the Spanish National Cancer Research Center in Madrid reported June 30 in Proceedings of the National Academy of Sciences. These mice with higher levels of SirT1 eat more but also burn more calories than do mice with normal levels of the enzyme.
But Longo’s group reported in the July Cell Metabolism that SirT1 may affect the brain differently. Neurons grown in the laboratory were sensitive to oxidative damage when they made normal amounts of SirT1, but reducing the amount of the enzyme helped the brain cells better resist stress.
“This is backwards,” says Leonard Guarente, a molecular and cellular biologist at MIT. Sirtuins are generally thought to protect cells against oxidative damage believed to play a part in aging. Guarente was not involved in any of the current studies, but his lab pioneered studying aging in yeast. “It’s intriguing, but it will take a little more time to figure out what it means in the context of other evidence to the contrary,” he says.
Mice can’t dispense with SirT1 entirely, though. Longo’s group found that mice from which the SirT1 gene was removed entirely died young. Calorie restriction did not lengthen their lives as it does for yeast lacking the similar gene, Sir2.
If SirT1 really makes neurons vulnerable, that’s potentially bad news for resveratrol. The chemical is found in small amounts in grapes, red wine and other foods and is thought to be the component in red wine responsible for the “French paradox” —in which people who eat a high-fat diet are protected from heart disease by consuming wine. Resveratrol has been shown to keep obese mice healthy enough to live a normal life-span (for a mouse). It has been thought to work in the same way as calorie restriction — by activating sirtuins. Sirtuins then modify other proteins, which, in turn, regulate genes involved in inflammation, immunity, stress responses and other processes of aging.
Indeed, an international group of researchers led by Rafael de Cabo at the U.S. National Institute on Aging reported in the July Cell Metabolism that mice fed resveratrol had similar patterns of gene activity as mice fed only every other day. The resveratrol-treated mice had better bone health, less cataract formation and improved coordination compared with other mice their age. Resveratrol also lowered the mice’s cholesterol and made their hearts function better compared with aged mice fed a standard diet. The findings echo others showing the health benefits of calorie restriction and of increased levels of SirT1.
Unfortunately, “the health benefits resveratrol gives these mice are not the things they are dying of,” de Cabo says. Mice generally die of cancer, not heart disease the way humans do. The mice don’t live longer when given resveratrol probably because the chemical doesn’t fight cancer the way calorie restriction seems to.
So far, resveratrol has shown no toxic side effects either in animal or human studies, de Cabo says. And while he takes Longo’s findings seriously, he says resveratrol is likely to have other actions besides just increasing SirT1 activity.
In fact, Tomas Prolla of the University of Wisconsin–Madison and colleagues suggest that resveratrol doesn’t work through SirT1 at all. In a paper published June 4 in PLoS ONE, Prolla’s group reports that resveratrol mimics some of the effects of calorie restriction, but works differently in some crucial ways, such as in how it regulates glucose uptake by muscles. That process is important in the development of diabetes and other medical problems. The compound did not prevent or slow down tumors in the mice.
But the group demonstrated that even at very low doses, resveratrol is a powerful protector of the heart.
To achieve extension of the maximum human life-span, though, scientists will have to develop a way to prevent cancer too, because “humans, like mice, under normal conditions do develop tumors as a consequence of aging,” Prolla says.
But he is optimistic. “I have no doubt the aging process will be understood at the molecular level and we can do something about it,” Prolla says.
Wednesday, May 20, 2009
Thursday, May 14, 2009
pylori 4.pyl.3 Louis J. Sheehan, Esquire
Children infected with a common stomach bacterium are less likely to have asthma than other kids, according to a study that will appear in the Aug. 15 Journal of Infectious Diseases.
The bug in question, Helicobacter pylori, is a microbe with a history like no other. A longtime resident of the human stomach, H. pylori went largely undetected until Australian scientists discovered it in 1979 and went on to show that it can cause stomach ulcers. Further work has linked it to stomach cancer. It’s now treated with antibiotics whenever detected.
Because H. pylori had been hitchhiking in humans for so long — possibly 50,000 years or more — microbiologist Martin Blaser of New York University became interested in the possible consequences of knocking it out.
He suspected that widespread antibiotic use has been suppressing H. pylori infections in industrialized countries over the past half century. During that same time, asthma has increased markedly.
Blaser and his colleague Yu Chen analyzed a database of health information obtained from people who enrolled in a national health study in either 1999 or 2000. The researchers focused on children, identifying 4,787 who didn’t have an H. pylori infection upon entering the study and 2,625 others who did. Questionnaires completed by study participants (or their parents) showed that children ages 3 to 13 with H. pylori were less than half as likely to have had asthma as were kids without an H. pylori infection.
Children with H. pylori were even less likely to have had, in the previous year, a bout of allergic rhinitis, which is marked by a runny nose, itchy eyes and inflamed nasal passages. And they were less apt to suffer from wheezing, the researchers report.
Blaser cautions that the association does not prove that an H. pylori infection prevents asthma, a chronic condition in which lung passages can become inflamed by contact with an allergen, smoke, pet dander or any number of other substances. Like allergies, asthma is an overreaction of the immune system to an innocuous substance.
Nevertheless, it’s possible that an H. pylori infection might somehow quell the immune system, Blaser says, or more likely induce the production of compounds that do. Or, H. pylori might just be a marker of something else that protects against asthma, he says.
It’s unclear how H. pylori spreads, but children living in messier households could have more H. pylori infections, says gastroenterologist David Graham of the Baylor College of Medicine and at the Michael E. DeBakey Veterans Affairs Medical Center, both in Houston. Thus, its apparent antiasthma effect might actually result from poor hygiene, he says.
Under a school of thought called the hygiene hypothesis, children who grow up in squeaky clean environments have more asthma and allergies than do kids raised in contact with farm animals or in other less sanitary conditions. The idea is that the immune systems of children in messy environments get regular challenges and thus mature properly.
Even if H. pylori did prevent asthma, the infection is not worth having, Graham says. “One would not allow king cobras to live in one’s house just because they might eat rats,” he says. “H. pylori is a king cobra equivalent in terms of the harm done to humans.”
Louis J. Sheehan, Esquire Patients would be better served if doctors could find a way to condition the immune system to achieve the effect of a dirty environment without the negative consequences, Graham says.
The bug in question, Helicobacter pylori, is a microbe with a history like no other. A longtime resident of the human stomach, H. pylori went largely undetected until Australian scientists discovered it in 1979 and went on to show that it can cause stomach ulcers. Further work has linked it to stomach cancer. It’s now treated with antibiotics whenever detected.
Because H. pylori had been hitchhiking in humans for so long — possibly 50,000 years or more — microbiologist Martin Blaser of New York University became interested in the possible consequences of knocking it out.
He suspected that widespread antibiotic use has been suppressing H. pylori infections in industrialized countries over the past half century. During that same time, asthma has increased markedly.
Blaser and his colleague Yu Chen analyzed a database of health information obtained from people who enrolled in a national health study in either 1999 or 2000. The researchers focused on children, identifying 4,787 who didn’t have an H. pylori infection upon entering the study and 2,625 others who did. Questionnaires completed by study participants (or their parents) showed that children ages 3 to 13 with H. pylori were less than half as likely to have had asthma as were kids without an H. pylori infection.
Children with H. pylori were even less likely to have had, in the previous year, a bout of allergic rhinitis, which is marked by a runny nose, itchy eyes and inflamed nasal passages. And they were less apt to suffer from wheezing, the researchers report.
Blaser cautions that the association does not prove that an H. pylori infection prevents asthma, a chronic condition in which lung passages can become inflamed by contact with an allergen, smoke, pet dander or any number of other substances. Like allergies, asthma is an overreaction of the immune system to an innocuous substance.
Nevertheless, it’s possible that an H. pylori infection might somehow quell the immune system, Blaser says, or more likely induce the production of compounds that do. Or, H. pylori might just be a marker of something else that protects against asthma, he says.
It’s unclear how H. pylori spreads, but children living in messier households could have more H. pylori infections, says gastroenterologist David Graham of the Baylor College of Medicine and at the Michael E. DeBakey Veterans Affairs Medical Center, both in Houston. Thus, its apparent antiasthma effect might actually result from poor hygiene, he says.
Under a school of thought called the hygiene hypothesis, children who grow up in squeaky clean environments have more asthma and allergies than do kids raised in contact with farm animals or in other less sanitary conditions. The idea is that the immune systems of children in messy environments get regular challenges and thus mature properly.
Even if H. pylori did prevent asthma, the infection is not worth having, Graham says. “One would not allow king cobras to live in one’s house just because they might eat rats,” he says. “H. pylori is a king cobra equivalent in terms of the harm done to humans.”
Louis J. Sheehan, Esquire Patients would be better served if doctors could find a way to condition the immune system to achieve the effect of a dirty environment without the negative consequences, Graham says.
Monday, May 4, 2009
news 9.new.23 Louis J. Sheehan, Esquire
When doctors are looking to treat an illness, they often rely on reports in medical journals. Sometimes those reports describe striking successes with a particular therapy. Less frequently, they highlight failures. To physicians, learning what doesn’t work or has troubling side effects can be as important as knowing which therapies hit a home run.
Yet doctors — and the reporters who highlight research news — are getting a very skewed picture of research findings if they rely on what makes it into major medical journals.
The reason: Data from fewer than one in five research trials are ever published. Findings from the vast majority of human trials become buried for reasons that may never come to light, according to a new study in The Oncologist. It’s published early and online September 24.
For the past nine years, the National Institutes of Health have maintained a registry of medical trials. Researchers must list theirs with this ClinicalTrials.gov registry. If they don’t, major medical journals (those that belong to the International Committee of Medical Journal Editors) will not publish the trial’s findings.
Scott Ramsey and John Scoggins of the University of Washington, Seattle, scoured that registry for any trial that was supposed to have been conducted to gauge the effectiveness of cancer treatments — and turned up 2,028. The pair then cross-checked these trials against all published studies that were listed in PubMed, a comprehensive database compiled by the National Library of Medicine. http://LOUIS2J2SHEEHAN.US PubMed includes citations to all medical and related studies that have been published in peer-reviewed journals.
Among the cancer trials that were identified as completed or halted as of a year ago, just 17.6 percent were ultimately published in PubMed-listed journals, Ramsey and Scoggins report.
Okay, maybe the halted trials were pulled because of what turned out to be poor research design, failure to recruit enough patients, or some other reasonable issue. But even after restricting the analysis to only those trials that were completed, the share that ended up being published still amounted to fewer than one in five.
Who conducted a trial seemed to influence the likelihood its data would see the light of day. Studies sponsored by industry (such as drug companies) had the lowest publication rate: 5.9 percent. By comparison, data from 59 percent of studies performed by clinical-trial networks were published.
Ramsey and Scoggins turned up 341 cancer trials from the registry that were published. Of these, two-thirds reported positive — expected and beneficial — findings.
The new analysis raises the ugly specter of publication bias, its authors say. The assumption is that many if not most unpublished trials involved treatments that didn’t work. “Of particular concern,” they argue, is the especially poor showing by industry-sponsored trials, since they tended to probe the value of patented drugs — “many of which are in clinical use.”
James H. Doroshow, director of the National Cancer Institute’s division of treatment and diagnosis, notes that last year alone some 50,000 patients took part in trials that his institute funded. The “apparent lack of access to the final efficacy and toxicity data for cancer clinical trials from all sponsors, but especially for industry-sponsored studies, poses multiple scientific and ethical questions,” he charges in an editorial accompanying the new paper.
For instance, as doctors begin developing novel chemotherapy cocktails — mixtures of drugs initially tested on their own — toxic reactions may emerge. It’s imperative, Doroshow says, that inklings of such side effects be communicated immediately “to the entire oncology community in the peer-reviewed literature.”
Moreover, he notes that some drug-safety trials did not publish their findings, or did not do so early enough, such that they could inform subsequent trials. This practice is not likely to continue, he points out, since new federal rules will fine investigators who fail to post outcome data for all trials getting money from Uncle Sam. Moreover, for cancer trials, NCI will require that researchers begin reporting outcome data — treatment successes and failures — throughout the course of the trial, not just at the end.
A second editorial, this one by The Oncologist’s senior editor, Gregory A. Curt (an employee of drug company AstraZeneca), and editor-in-chief Bruce A. Chabner (of Harvard Medical School) find the new analysis by Ramsey and Scoggins “thought-provoking and disturbing.” At a minimum, they argue, publication of trial data should be considered “an obligation” for any researchers recruiting patients who contribute “their precious time and well-being, and for some, their very lives.”
This is especially true for drug-company trials, they contend, since “industry has become the dominant sponsor of new drug trials.”
But Curt and Chabner also suspect that part of the problem illustrated in the new paper traces to issues other than a drug company’s interest in hiding bad data.
For instance, study authors “face the hurdle of finding a journal willing to publish a negative, poorly designed or inadequately accruing trial.” This is especially true, they say, since “Journals live and die based on their Impact Factor” — how often they’re cited by subsequent papers. Any journal filled with such findings would “not attract readership, citations and advertisement,” they write.
One solution Curt and Chabner propose: Make NCI funding for new trials dependent on the investigators’ past track record of getting their trials data — both positive and negative — published. They also argue that there’s “a need for a new venue” to record outcomes of well-executed but ultimately negative clinical trials. This database must be searchable via PubMed and other search engines. Louis J. Sheehan, Esquire Currently, these editors note, The Oncologist is considering whether it should become a repository for such cancer data.
Bottom line: It should become increasingly harder for drug companies and others to bury embarrassing findings. But the impacts of coming changes might not show up for five years or more. In the mean time, let’s hope our research-funding agencies, our hospitals and our doctors don’t assume that when it comes to trial data, no news is good news.
Yet doctors — and the reporters who highlight research news — are getting a very skewed picture of research findings if they rely on what makes it into major medical journals.
The reason: Data from fewer than one in five research trials are ever published. Findings from the vast majority of human trials become buried for reasons that may never come to light, according to a new study in The Oncologist. It’s published early and online September 24.
For the past nine years, the National Institutes of Health have maintained a registry of medical trials. Researchers must list theirs with this ClinicalTrials.gov registry. If they don’t, major medical journals (those that belong to the International Committee of Medical Journal Editors) will not publish the trial’s findings.
Scott Ramsey and John Scoggins of the University of Washington, Seattle, scoured that registry for any trial that was supposed to have been conducted to gauge the effectiveness of cancer treatments — and turned up 2,028. The pair then cross-checked these trials against all published studies that were listed in PubMed, a comprehensive database compiled by the National Library of Medicine. http://LOUIS2J2SHEEHAN.US PubMed includes citations to all medical and related studies that have been published in peer-reviewed journals.
Among the cancer trials that were identified as completed or halted as of a year ago, just 17.6 percent were ultimately published in PubMed-listed journals, Ramsey and Scoggins report.
Okay, maybe the halted trials were pulled because of what turned out to be poor research design, failure to recruit enough patients, or some other reasonable issue. But even after restricting the analysis to only those trials that were completed, the share that ended up being published still amounted to fewer than one in five.
Who conducted a trial seemed to influence the likelihood its data would see the light of day. Studies sponsored by industry (such as drug companies) had the lowest publication rate: 5.9 percent. By comparison, data from 59 percent of studies performed by clinical-trial networks were published.
Ramsey and Scoggins turned up 341 cancer trials from the registry that were published. Of these, two-thirds reported positive — expected and beneficial — findings.
The new analysis raises the ugly specter of publication bias, its authors say. The assumption is that many if not most unpublished trials involved treatments that didn’t work. “Of particular concern,” they argue, is the especially poor showing by industry-sponsored trials, since they tended to probe the value of patented drugs — “many of which are in clinical use.”
James H. Doroshow, director of the National Cancer Institute’s division of treatment and diagnosis, notes that last year alone some 50,000 patients took part in trials that his institute funded. The “apparent lack of access to the final efficacy and toxicity data for cancer clinical trials from all sponsors, but especially for industry-sponsored studies, poses multiple scientific and ethical questions,” he charges in an editorial accompanying the new paper.
For instance, as doctors begin developing novel chemotherapy cocktails — mixtures of drugs initially tested on their own — toxic reactions may emerge. It’s imperative, Doroshow says, that inklings of such side effects be communicated immediately “to the entire oncology community in the peer-reviewed literature.”
Moreover, he notes that some drug-safety trials did not publish their findings, or did not do so early enough, such that they could inform subsequent trials. This practice is not likely to continue, he points out, since new federal rules will fine investigators who fail to post outcome data for all trials getting money from Uncle Sam. Moreover, for cancer trials, NCI will require that researchers begin reporting outcome data — treatment successes and failures — throughout the course of the trial, not just at the end.
A second editorial, this one by The Oncologist’s senior editor, Gregory A. Curt (an employee of drug company AstraZeneca), and editor-in-chief Bruce A. Chabner (of Harvard Medical School) find the new analysis by Ramsey and Scoggins “thought-provoking and disturbing.” At a minimum, they argue, publication of trial data should be considered “an obligation” for any researchers recruiting patients who contribute “their precious time and well-being, and for some, their very lives.”
This is especially true for drug-company trials, they contend, since “industry has become the dominant sponsor of new drug trials.”
But Curt and Chabner also suspect that part of the problem illustrated in the new paper traces to issues other than a drug company’s interest in hiding bad data.
For instance, study authors “face the hurdle of finding a journal willing to publish a negative, poorly designed or inadequately accruing trial.” This is especially true, they say, since “Journals live and die based on their Impact Factor” — how often they’re cited by subsequent papers. Any journal filled with such findings would “not attract readership, citations and advertisement,” they write.
One solution Curt and Chabner propose: Make NCI funding for new trials dependent on the investigators’ past track record of getting their trials data — both positive and negative — published. They also argue that there’s “a need for a new venue” to record outcomes of well-executed but ultimately negative clinical trials. This database must be searchable via PubMed and other search engines. Louis J. Sheehan, Esquire Currently, these editors note, The Oncologist is considering whether it should become a repository for such cancer data.
Bottom line: It should become increasingly harder for drug companies and others to bury embarrassing findings. But the impacts of coming changes might not show up for five years or more. In the mean time, let’s hope our research-funding agencies, our hospitals and our doctors don’t assume that when it comes to trial data, no news is good news.
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